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Cross-linking of the cornea is a new curative approach to re-increase the mechanical stability of corneal tissue that is progressively decreasing as a result of a corneal disease such as keratoconus or pellucid marginal degeneration. The new procedure might have the potential to reduce the need for invasive corneal transplantation. The aim of the treatment is to create additional chemical bonds inside the corneal stroma by means of a photopolymerizer and UV light at 365 nm. Two different potential damage mechanisms must be considered: the UV-irradiation alone and the action of the photochemically induced free radicals (photochemical damage). In this study damage thresholds from the literature were compared to the treatment parameters currently used in corneal cross-linking and aspects of the design of a UV illumination system for corneal cross-linking were discussed with respect to the safety of the procedure. It was shown that the currently used UVA dose density of 5.4 mJ/cm2 is below the known damage thresholds of UVA for the corneal endothelium, lens, and retina. All these safety considerations assume an optically homogeneous irradiation. Optical inhomogeneities such as hot spots may lead to localized supra-threshold irradiation with consecutive damage to the corneal endothelium which represents the most endangered structure. Some authors have used direct illumination of the cornea by means of UV-LEDs, which bares the risk of creating too high intensities. Therefore, clinically used light sources must guarantee a perfect homogeneity of the irradiance across the beam area. The illumination system presented here provides good homogeneity and shows a very high tolerance towards variations in treatment distance which was shown to cause dangerous hot spots when direct LED illumination is used.